Discovery of a First-In-Class Small Molecule Antagonist against the Adrenomedullin‑2 Receptor: Structure–Activity Relationships and Optimization

Class B G-protein-coupled
receptors (GPCRs) remain an underexploited
target for drug development. The calcitonin receptor (CTR) family
is particularly challenging, as its receptors are heteromers comprising
two distinct components: the calcitonin receptor-like receptor (CLR)
or calcitonin receptor (CTR) together with one of three accessory
proteins known as receptor activity-modifying proteins (RAMPs). CLR/RAMP1
forms a CGRP receptor, CLR/RAMP2 forms an adrenomedullin-1 (AM1) receptor, and CLR/RAMP3 forms an adrenomedullin-2 (AM2) receptor. The CTR/RAMP complexes form three distinct amylin
receptors. While the selective blockade of AM2 receptors
would be therapeutically valuable, inhibition of AM1 receptors
would cause clinically unacceptable increased blood pressure. We report
here a systematic study of structure–activity relationships
that has led to the development of first-in-class AM2 receptor
antagonists. These compounds exhibit therapeutically valuable properties
with 1000-fold selectivity over the AM1 receptor. These
results highlight the therapeutic potential of AM2 antagonists.